Osteoarthritis is a degenerative joint disease affecting articular cartilage developing in the fourth and fifth decades of life that was initially believed to be a disease of wear and tear due to mechanical stress on the joints. It is now known that the pathology of osteoarthrosis is not entirely mechanical and involves changes in the joint metabolism. Specifically, altered glucosamine metabolism appears to play a key role in the development of osteoarthritis.
An effective treatment of osteoarthritis must address two types of problems: (i) pain, and joint tenderness, swelling and stiffness must be alleviated as an immediate patient's problem; and (ii) the degenerative process must be stopped preferably at its earlier stages. Treatment with anti-rheumatics and nonsteroidal anti-inflammatory drugs has not proven successful. Anti-rheumatics, although quickly effective, were recently shown to impair the very function that physicians were trying to improve, and anti-inflammatory drugs alleviate the pain but do not address the underlying degenerative disorder.
Recent biochemical and pharmacological studies have suggested a novel and more effective treatment of osteoarthritis. These studies have shown that administration of glucosamine tends to normalize cartilage metabolism, inhibiting degradation, and stimulating the synthesis of proteoglycans resulting in partial restoration of the articular function. The therapeutic effectiveness of a treatment with glucosamine has been demonstrated in a number of animal and human studies.
Glucosamine is a building block of the ground substance of the articular cartilage, the proteoglycans. Glucosamine is also the preferential substrate and a stimulant of proteoglycan biosynthesis. Furthermore, glucosamine inhibits the degradation of proteoglycans and rebuilds the experimentally damaged cartilage. Based on these findings, different types of glucosamine were introduced in the therapy of osteoarthritis. The clinical experience with preparations containing glucosamine derivatives confirmed the efficacy and the safety of the glucosamine treatment. The following is a brief summary of recent developments concerning the use of glucosamine sulfate to treat osteoarthritis.
Glucosamine sulfate is an artificially synthesized salt of glucosamine. Based on animal models, glucosamine sulfate has the potential to slow the degeneration of cartilage by stimulating cartilage cells to synthesize glucosamine, glycans and proteoglycans, the building components of cartilage. See Setnikar et al., Anti-Arthritic Effects of Glucosamine Sulfate Studied in Animal Models, Drug Research, 41:542-549 (1991). This study has also reported that glucosamine sulfate has anti-inflammatory properties by acting through a mechanism that inhibits the activity of proteolytic enzymes.
In the early 1980s, a number of small controlled human trials were conducted to study the clinical use of glucosamine sulfate in the treatment of osteoarthritis. Scientists evaluated glucosamine sulfate both as a symptomatic treatment and as a basic therapy to slow the underlying degenerative process. See Vaz, A. L., Double Blind Clinical Evaluation of the Relative Efficacy of Ibuprofen and Glucosamine Sulfate in the Management of Osteoarthritis of the Knee in Out-patients, Curr. Med. Res. Opin., 8:145-149 (1982); Vajaradul, Y., Double Blind Clinical Evaluation of Intra-Articular Glucosamine in Outpatients with Gonarthrosis, Clin. Therapeutics, 3:336-343 (1981); Pujalte, A.M., et al., Double Blind Clinical Evaluation of Oral Glucosamine Sulfate in the Basic Treatment of Osteoarthrosis, Curr. Med. Res. Opin., 7:1010-1014 (1980); Crolle, G. and D'Este, E., Glucosamine Sulfate for the Management of Arthrosis: A Controlled Clinical Investigation, Curr. Med. Res. Opin., 7:104-109 (1980).
These studies have shown that administration of glucosamine sulfate produces significant improvement in the symptoms of pain, joint tenderness, swelling and mobility. In addition, the treatment helped restore the patients' cartilage. Furthermore, the treatment was shown not to have any adverse side effects or undesirable interactions with other drugs normally used by elderly arthritic patients.
Glucosamine sulfate can be administered by interarticular, intramuscular and intravenous injection as well as orally. See D'Ambrosio et al., In Glucosamine Sulfate: a Controlled Clinical Investigation in Arthrosis, Pharmatherapeutica, 2:504-508 (1981). Vagaradul, Y., Clin. Therapeutics, 3:336-343 (1981), has reported a combination treatment using both intramuscular and oral administration. In all reported clinical trials oral glucosamine sulfate was administered at 1.5 g/day. For example, Pujalte teaches administration of 500 mg of glucosamine sulfate three times a day for a period of 6 to 8 weeks. Crolle teaches administration of one intramuscular injection of glucosamine sulfate (400 mg/day) for 7 days followed by oral administration of 500 mg of glucosamine sulfate three times a day for a period of 14 days. Vaz discloses an 8 week treatment by oral administration of 500 mg of glucosamine sulfate three times a day. The dose of 1.5 g glucosamine sulfate is equivalent to about one gram of D-glucosamine base.
The bioavailability of glucosamine was studied extensively. A number of studies reported the pharmacokinetics, organ distribution, metabolism and excretion of glucosamine. The studies were done in dog, rat and man. See Setnikar, I., et al., Pharmacokinetics of Glucosamine in the Dog and Man, Arzneim-Forsch/Drug Res. 36:729-35 (1986); Setnikar, I. et al., Absorption, Distribution and Excretion of Radioactivity After a Single Intravenous or Oral Administration of [14]C Glucosamine to the Rat, Pharmatherapeutica, 3:538-50 (1984); Levin, R. et al., Glucosamine and Acetyl-Glucosamine Tolerance in Man; J. Lab. Clin. Med, 59:927-931 (1961); Gaulden, E. C. and Keating, W. C., The Effect of Intravenous N-acetyl-D-Glucosamine on the Blood and Urine Sugar Concentration of Normal Subjects, Metabolism, 13:466-472 (1964); Kohn P. et al., Metabolism of D-Glucosamine and N-acetyl-D-Glucosamine in the Intact Rat, J. Bio. Chem., 237:304-307 (1962); Weiden, S. and Wood, I.J., The Fate of Glucosamine Hydrochloride Injected Intravenously in Man, J. Clin. Path. 11:343-349 (1958).
These studies have shown that glucosamine is found in the plasma immediately after intravenous administration, from where it readily diffuses into organs and tissues. See Setnikar et al. (1986). In both dog and man, glucosamine disappears quickly from plasma, usually after 30 to 60 minutes, and gets incorporated into .alpha. and .beta. globulins. The protein incorporation of glucosamine reaches a peak after 8 hours and slowly disappears, having a half-life of 2.9 days. The glucosamine is excreted 34% in urine mainly as glucosamine and 1.7% in the feces. It is also degraded and excreted as CO.sub.2. The liver and kidney show significant incorporation of glucosamine. In addition, the articular cartilage shows an active uptake. Setnikar also teaches that the distribution of glucosamine after oral administration is similar to the distribution after the intravenous administration. In addition, these studies have shown that N-acetyl-D-glucosamine (NAG) metabolizes in the body to glucosamine.
Other studies have also shown that the half-life of glucosamine in the blood is relatively short due to its degradation and/or incorporation into other bodily compounds. See Gaulden and Keating; Weiden et al.; and Levin et al. Accordingly, it is difficult to maintain adequate therapeutic levels in vivo which requires prolonged treatments and multiple daily administrations.
It has now been surprisingly discovered that poly-N-acetyl-D-glucosamine (poly-NAG), can be used as a source of glucosamine to treat osteoarthritis and/or alleviate symptoms thereof. This is surprising since it is generally known that poly-NAG is highly resistant to chemical attack except that of a most drastic nature. Furthermore, it was surprisingly discovered that individuals who ingest poly-NAG have higher serum levels of NAG and glucosamine. Poly-NAG maintains these serum levels for a longer period of time than when NAG is ingested alone and therefore provides a longer lasting source of glucosamine for the treatment of osteoarthritis. Thus, treatment with poly-NAG offers unexpected advantages over the prior art treatments with glucosamine and NAG.
In addition, poly-NAG, which need not be highly refined and purified, is considerably cheaper than glucosamine and NAG. According to the 1995 Sigma Chemical Company catalogue, the price of poly-NAG (chitin) is $55/kg, while glucosamine and NAG cost $86/kg and $391/kg, respectively. Commercial quantities of poly-NAG suitable for ingestion may be obtained at an even lower price ($25/kg). Accordingly, treatment with poly-NAG also offers the cost advantages over the prior art treatments with glucosamine and NAG.